Gut fungi teach the immune system how to deal with their dangerous relatives

Common fungi, often present in the gut, teach the immune system how to deal with their most dangerous relatives, according to a new study from scientists at Weill Cornell Medicine. Disruption of this process can leave people vulnerable to deadly fungal diseases.

The study, published on February 5 in Cell, reveals a new twist in the complex relationship between humans and the microbes associated with them, and marks the path towards novel cures that can fight off a host of pathogens that is drug resistant.

This new discovery came from work on an infectious bowel disease, which often causes patients to carry larger than normal numbers of fungi in their legs. These patients often develop strong responses against manna, a molecule that is common to a wide range of fungal species. However, Dr. Iliyan Iliev, associate professor of immunology in medicine in the Department of Gastroenterology and Hepatology at Weill Cornell Medicine, noted that healthy controls also contained some anti-fungal antibodies in these studies.

There was no real evidence for fungal infections in the healthy people we studied, so we started thinking about the possible role of these antibodies. “

Dr. Iliev, Lead Author Study, Member, Jill Roberts Institute for Research on Infectious Infectious Disease

The team developed a platform that allowed them to determine which gut fungi are targeted by antibodies in the blood of individual patients. They found a strong response against the yeast Candida albicans.

Turning to experiments in mice, Dr. Iliev and Itai Doron, doctoral candidate at Weill Cornell Graduate School of Medicine in the laboratory and lead author of the study, found that colonies of animals with Candida albicans caused them to develop antibodies . the fungus in their bloodstream, even though they did not develop fungal infections with blood. Instead, the immune cells of the animals appeared to carry fungal antigens to the spleen, stimulating the production of circulating antibodies in the bloodstream. “These fungi are just educating that immune response,” Dr. Iliev said.

In patients with immune systems, such as organ transplants and some cancer patients, fungi in the gut can attack blood flow and cause life-threatening diseases. Dr. Iliev and his colleagues explained this process by treating mice with immunosuppressive drugs. When the Candida species settles in the gut of these mice, the fungus moves into the bloodstream, causing a fatal infection.

Treating the mice with pure anti-fungal antibodies from donor animals protected the immune-immune mice from these diseases. The same strategy worked against infection either with Candida albicans or with the pathogenic yeast Candida auris, which has been a leading cause of fungal infection in vaccinated patients and the elderly in recent years. .

Collaborating with researchers at INSERM in Paris, France, the Weill Cornell Medicine team also looked at a serum from patients with mutations in a gene called CARD9. This mutation affects the emergency adapter protein in the immune system, leaving those affected prone to severe fungal infections. Dr. Iliev’s team found that the serum of these patients was not deficient in anti-fungal antibodies commonly found in patients’ serum without this imitation. Tests in mice have confirmed an essential and specific role for CARD9 in priming the production of anti-fungal antibodies.

Graphic illustration showing relationship between fungi in gut, antibody levels and CARD gene Relationship between gut fungi, anti-fungal antibodies, CARD9 gene, and fungal immunity. Image courtesy of Iliev Laboratory.

The findings suggest that normal intestinal fungi such as Candida albicans may act as a form of intestinal vaccine against fungal infection in healthy individuals, by stimulating blood production that may target several species of potentially pathogenic fungi. When these fungi enter the bloodstream, the antibodies bind and target them for destruction by immune system cells. In patients with suppressed immunity, the anti-fungal antibodies can decay, leaving them vulnerable to fungal infections.

New therapies that include either stimulating the production of anti-fungal antibodies, or injecting such purified antibodies into a patient’s bloodstream, may help to resistance to these increasingly common diseases.

If that approach works, it would be a welcome improvement. “Many fungal infections in vaccinated and elderly patients occur by removal of pathogenic Candida strains from the gastrointestinal tract, and survival rates at systemic transmission are extremely low,” Dr. Iliev said.